Metabolic syndrome is characterized by a group of metabolic risk factors in one person including abdominal obesity, insulin resistance or glucose intolerance, atherogenic dyslipidemia, prothrombotic state, proinflammatory state and hypertension. The Adult Treatment Panel defines metabolic syndrome as present if a patient manifests at least three of the following symptoms: waist measuring at least 40 inches for men, 35 inches for women; serum triglyceride levels of at least 150 mg/dl; HDL cholesterol levels of less than 40 mg/dl in men, less than 50 mg/dl in women, blood pressure of at least 135/80 mm Hg and blood sugar (serum glucose) of at least 110 mg/dl. It has been estimated that up to 25% of the population in the United States are afflicted with metabolic syndrome.
An underlying cause of metabolic syndrome is believed to be insulin resistance wherein the ability of insulin to take in glucose from the blood is attenuated. This causes glucose levels to remain elevated after eating to which the pancreas responds by excreting insulin. If left untreated, metabolic syndrome significantly increases the risk of type II diabetes, cardiovascular disease and other diseases related to plaque buildups in artery walls.
An inverse correlation between fasting insulin levels and serum testosterone in men has been demonstrated by several studies. Moreover, serum testosterone is significantly lower in men with metabolic syndrome and other insulin-resistant states such as obesity and type 2 diabetes mellitus compared to controls. The mechanism underlying these observations, however, has not been elucidated.
One recent study has suggested that the relationship between testosterone and insulin may be mediated through changes in the body mass index (BMI) wherein low testosterone levels lead to obesity and dysregulation of fatty acid metabolism which in turn promotes insulin resistance. In contrast to testosterone, no significant relationship between estrogen levels and insulin sensitivity was found in that study.
Another recent study evaluated the hypothalamic-pituitary-gonadal axis in men with a broad spectrum of insulin sensitivity. In this study, a positive relationship between insulin sensitivity and testosterone was observed, however, no relationship was observed between insulin sensitivity and luteinizing hormone (LH) secretion parameters suggesting that low testosterone associated with insulin resistance does not result from a defect in the hypothalamus or pituitary, but rather from an alteration in Leydig cell function. In this regard, it well established that Leydig cell steroidogenesis, at least in vitro, is modulated not only by pulsatile secretion of LH but also by hormones, growth factors, cytokines and insulin.
Data on the impact of androgen supplementation on insulin sensitivity in men are conflicting. In one study, men with type 2 diabetes showed no improvement in glycemic control with testosterone replacement, whereas a larger study showed a significant reduction in glycosylated hemoglobin.
Testosterone is the primary male androgen, playing a vital role in overall male health. Testosterone is essential to the development and maintenance of specific reproductive tissues (testes, prostate, epididymis, seminal vesicle, and penis) and male secondary sex characteristics. It plays a key role in libido and erectile function and is necessary for the initiation and maintenance of spermatogenesis.
Testosterone secretion is the end product of a series of hormonal processes. Gonadotropin-releasing hormone (GnRH), which is secreted in the hypothalamus, controls the pulsatile secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which is secreted by the anterior pituitary. LH, in turn, regulates the production and secretion of testosterone in the Leydig cells of the testes, while FSH assists in inducing spermatogenesis.
Testosterone deficiency can result from underlying disease or genetic disorders and is also frequently a complication of aging. For example, primary hypogonadism results from primary testicular failure. In this situation, testosterone levels are low and levels of pituitary gonadotropins (LH and FSH) are elevated. Secondary or hypogonadotrophic hypogonadism is due to inadequate secretion of the pituitary gonadotropins. In addition to a low testosterone level, LH and FSH levels are low or low-normal. Some of the sequelae of adult testosterone deficiency include a wide variety of symptoms including: loss of libido, erectile dysfunction, oligospermia or azoospermia, absence or regression of secondary sexual characteristics, progressive decrease in muscle mass, fatigue, depressed mood and increased risk of osteoporosis. Many of these disorders are generically referred to as male menopause.
Clomiphene (FIG. 2), which is an antiestrogen related to tamoxifen, has also been used to treat men with low testosterone levels. Clomiphene blocks the normal estrogen feedback on the hypothalamus and subsequent negative feedback on the pituitary. This leads to increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH). In men, these increased levels of gonadotropins stimulate the Leydig cells of the testes and result in the production of higher testosterone levels.
Tenover et al., J. Clin. Endocrinol. Metab. 64:1103, (1987) and Tenover et al., J. Clin. Endocrinol. Metab. 64:1118 (1987) found increased in FSH, LH in both young and old men after treatment with clomiphene. They also found increases in free and total testosterone in men with young men showing significant increases.
Ernst et al., J. Pharmaceut. Sci. 65:148 (1976), have shown that clomiphene is a mixture of two geometric isomers which they refer to as cis,-Z-, clomiphene (cis-clomiphene or zuclomiphene) and trans-,E-, clomiphene, (trans-clomiphene or enclomiphene). According to Ernst, et al. trans-clomiphene HCI has a melting point of 149° C.-150.5° C., while cis-clomiphene HCI has a melting point of 156.5° C.-158° C. Ernst et al. have also noted that (the trans-isomer) is antiestrogenic (AE) while the cis-isomer is the more potent and more estrogenic form and has also been reported to have anti-estrogenic activity. The authors attribute the effect of the drug on ovulatory activity to both forms stating that the mixture is more effective than trans-clomiphene alone. The trans-isomer aids ovulation at the level of the hypothalamus. The estrogenic isomer cis-clomiphene contributes to enhanced ovulation elsewhere in the physiologic pathway leading to ovulation. The isomers are also reported to have different in vivo half-life. Furthermore the cis form has been reported to leave residual blood levels for in excess of one month following a single dose.
Clomiphene is currently approved as a mixture of both cis- and trans-isomers, the cis-isomer being present as about 30% to 50% (Merck Manual) for fertility enhancement in the anovulatory patient. Clomiphene improves ovulation by initiating a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The drug is recommended to be administered for 5 days at a dose of up to 100 mg daily. Clomiphene has also been associated with numerous side effects including: blurred vision, abdominal discomfort, gynecomastia, testicular tumors, vasomotor flushes, nausea, and headaches. Furthermore, other studies suggest that clomiphene possesses both genotoxic and tumor enhancement effects. The net outcome of these observations is that clomiphene in its current format, having between 30% and 50% of the cis isomer, would be unacceptable for chronic therapy in men for the treatment of testosterone deficiency.